Hormone dependent uterine epithelial-stromal communication for pregnancy support

Abstract

Human fertility is a relatively inefficient process. Despite the presence of visibly healthy embryos, 30% of pregnancies generated by assisted reproductive technology (ART) fail before the second trimester. The uterine microenvironment plays a critical role in establishing and maintaining a successful pregnancy that requires coordinated communication between the epithelial and stromal cells of the endometrium. The epithelial cells must cease proliferation and become permissive for the conceptus (embryo and associated extraembryonic membranes), while the stromal cells undergoes mesenchymal-to-epithelioid transformation to form the decidua in support of subsequent embryo development. The ovarian steroids Estrogen (E2) and Progesterone (P4) are the major hormones governing these processes. These hormones act via their nuclear receptors, the estrogen receptor, ESR1, and progesterone receptor, PGR, to direct the transcription of genes that orchestrate epithelial and stromal cell communication. This review will discuss the molecular mechanisms utilized by steroid hormones that regulate uterine receptivity, as well, establish and maintain pregnancy.

Keywords: Pregnancy; Progesterone; Uterine receptivity.

Fig. 1

Schematic digram of the window of receptivity governed by ovarian steroid progesterone (P₄) for uterine epithelial-stromal communication. PGR regulates growth factors that prime the stromal cells for decidualization, while stromal cells produce factors that control epihtelial cell proliferation. The crosstalk thereby allows conceptus attachment, invasion as well as establishment and maintenance of pregancy. LE, luminal epithelium.

Fig. 2

Epithelial PGR regulates multiple signaling pathways in the endometrium and transuduce signals via uterine epithelial-stormal inteactions. Epithelial PGR regualtes transcription of Ihh, which acts on stromal cells via its receptors, PTCH1 and PTCH2, as well as its downstream mediator COUP-TFII and stromal PGR. This pathway primes stromal cells for decidualization via BMP2 and WNT4. Induction of BMP2 and WNT4 also requires EGFR siganling. In addition, HAND2 expression is promoted directly by stromal PGR and COUP-TFII. HAND2 then inhibits prodution of FGF ligands, thereby stop proliferative signaling to the uterine epithelial cells. PGR, progesterone receptor; GATA2, GATA binding protein 2; IHH, indian hedgehog; PTCH1, patched 1; PTCH2, patched 2; COUP-TFII, chicken ovalbumin upstream transcription factor II; BMP2, bone morphogen protein 2; WNT4, Wnt family member 4; EGFR, epidermal growth factor receptor; HAND2, heart- and neural crest derivative-expressed protein 2; FGF, fibroblast growth factor.